Both acute and persistent pains are major public health concerns yet causes and prognoses are poorly understood. In addition to basic pain stimulus perception (i.e. nociception) genetic, endocrine, immunologic and nutritional factors are hypothesized to contribute. Women may be especially at risk. One putative risk factor is vitamin D deficiency, to which a variety of common bone and musculoskeletal pain syndromes have been linked. Moreover, vitamin D deficiency has been linked to increases in inflammatory markers which, in turn, have been linked to both acute and persistent pain. A better understanding of the relationship between inflammation and vitamin D is critically important to understanding pain itself and to devising cost-effective methods for screening and treating vitamin D deficiency. In this project we will combine assessment of vitamin D and inflammatory markers with measures of both clinical and evoked pain for a twin study that will allow us to estimate the relative contributions of vitamin D deficiency and inflammation to pain while controlling for genetic and common environmental influences. We will thus examine vitamin D levels, pro-inflammatory cytokines, and pain in 181 monozygotic (MZ) and 119 dizygotic (DZ) twin pairs (300 total pairs) from the community-based University of Washington Twin Registry (UWTR). To accomplish this we will tap into the unique resources of the UWTR which include stored plasma samples, pain phenotype data, and general health and sociodemographic data from the 300 twin pairs collected at a single study visit over the past five years. In addition, from those 300 pairs, pro-inflammatory cytokine assays (IL-1-beta, IL-6, and TNF-alpha) are already available from 127 MZ and 69 DZ pairs for a total of 196 pairs. Thus, using the stored plasma samples, we can generate vitamin D levels on all 300 pairs and pro-inflammatory cytokines levels on the 104 pairs for whom the assays have not yet been done. All the biological data can then be efficiently combined with concurrent physical examination and questionnaire data related to pain, health, and demographics for a unique and genetically informative study. The specific aims are 1) To assess within-pair differences in vitamin D and proinflammatory cytokine levels and their effect on both clinical and evoked pain responding in a sample of twins; 2) To assess between-pair differences to determine if the associations between vitamin D, pro- inflammatory cytokines, and clinical and evoked pain are due to genetics or common environmental factors; and 3) To evaluate gene x environment interactions related to seasonal sun exposure and adiposity. PUBLIC HEALTH RELEVANCE: A better understanding of the links between pain, inflammation, and vitamin D is critically important to understanding chronic pain itself and to devising cost-effective methods for screening for and treating vitamin D deficiency. Previous studies in this area have tended to be small, uncontrolled and not population-based. The proposed research will address these weaknesses by examining the relationship between vitamin D levels and pain in two sets of female twins from the community-based University of Washington Twin Registry. This research may especially benefit women, who may be especially at risk for certain forms of chronic pain.